A key event in an immune response involves the migration of leukocytes to a disease site. During an inflammatory response, leukocytes are recruited to the site of injury and are extravasated by a series of cellular interactions involving cell-cell and cell-substrate adhesion. The administration of compounds that inhibit these cellular interactions of leukocytes provides a route for treating inflammatory or immune diseases.
One family of molecules that serves an important adhesive function is integrins. Integrins are expressed on cell surfaces and function in cell-cell and cell-substrate adhesion. Integrins are alpha-beta heterodimers: each integrin has an alpha (α) subunit non-covalently bound to a beta (β) subunit. There are four known integrins having a β2 or CD18 subunit, which comprise the CD11/CD18 integrin subfamily, namely, Lymphocyte Function-associated Antigen 1 (LFA-1) (CD11a/CD18 or αLβ2); Macrophage Antigen 1 (Mac-1) (CD11b/CD18 or αMβ2); p150, 95 (CD11c/CD18 or αXβ2); and αDβ2. The CD11/CD18 family of integrins is also referred to as Leukointegrins as they are expressed on the surface of various leukocyte cells, and they mediate a number of inflammation-related cellular interactions. See Diamond et al., “The Dynamic Regulation of Integrin Adhesiveness,” Current Biology, Vol. 4 (1994) at pp. 506-532.
When activated, the integrins bind to extracellular ligands and induce adhesion. Ligands to LFA-1 and Mac-1 comprise the intercellular adhesion molecule (ICAM) ICAM-1. The primary CD11/CD18 integrin is LFA-1, which also binds with ICAM-2 and ICAM-3. The interaction between the CD18 integrins, particularly LFA-1, and ICAMs mediates antigen presentation, T-cell proliferation, and adhesion between the endothelium and activated leukocytes, which is necessary for leukocytes to migrate from the circulatory system into tissue. Compounds inhibiting CD18 integrins, ICAMs, and/or the LFA-1: ICAM interaction have demonstrated a wide range of utilities in treating inflammatory or immune diseases. Compounds that reportedly inhibit LFA-1/ICAM for use as anti-inflammatory agents include thiadiazole-based compounds (see Intern. Pub. No. WO 99/20,618, “Thiadiazole Amides Useful as Anti-Inflammatory Agents” filed by Pharmacia & Upjohn Co.; and WO 99/20,617, also to Pharmacia and Upjohn); and thiazole compounds linked to phenyl and pyrazole rings (Sanfilippo et al., “Novel Thiazole Based Heterocycles as Inhibitors of LFA-1/ICAM-1 Mediated Cell Adhesion,” J. Med. Chem., Vol. 38 (1995) at pp. 1057-1059). Small molecules that reportedly are antagonists to the binding of ICAMs with CD18 integrins include various benzylamines and 2-bromobenzoyltryptophan compounds (see Intern. Pub. No. W099/49,856, “Antagonists for Treatment of CD11/CD18 Adhesion Receptor Mediated Disorders, ” filed by Genentech, Inc.), and 1-(3,5 dichlorophenyl) imidazolidines (see Intern. Pub. No. WO98/39303, “Small Molecules Useful in the Treatment of Inflammatory Disease, ” filed by Boehringer Ingelheim Pharmaceuticals, Inc. See also Boehringer patent applications WO 01/07052, WO 01/07048, WO 01/07044, WO 01/06984, and WO 01/07440). Hydantoin compounds are disclosed in Intern. Pub. No's WO 00/59880, WO 00/39081, WO 02/02522, WO 02/02539 (all to Abbott Laboratories). LFA-1 antagonist compounds are also claimed in WO 02/059114 (to Genentech), WO 02/42294 (to Celltech), WO 01/51508 (to Science and Technology corporation), WO 00/21920 and WO 01/58853 (both to Hoffmann-LaRoche), WO 99/11258, WO 00/48989 and WO 02/28832 (all to Novartis). Hydantoin compounds are disclosed in Intern. Pub. No. WO 01/30781 A2 (published May 3, 2001) to Tanabe Seiyaku Co. Ltd, “Inhibitors of αLβ2 Mediated Cell Adhesion,” and in Intern. Pub. No. WO 02/44181 (published Jun. 6, 2002), “Hydantoin Compounds Useful as Anti-Inflammatory Agents”, to the present assignee and having common inventors herewith.
U.S. patent application Publication 2004/0009998 A1 (to present assignee), incorporated herein by reference, discloses aryl or heteroaryl substituted spiro-hydantoin compounds that are effective as antagonists of Leukointegrins and/or ICAMs. The reference also discloses various processes to prepare these spiro-hydantoins, such as a multistep synthesis that includes the introduction and subsequent removal of protecting groups.
However, there are recognized difficulties associated with the adaptation of the disclosed multistep synthesis for preparing such spiro-hydantoin compounds to larger scale, such as production in a pilot plant or on a manufacturing scale. Desired in the art is a process suitable for the production of these aryl or heteroaryl substituted spiro-hydantoin compounds in larger quantities than typically prepared by laboratory scale processes. Also desired is a process that optionally provides facile separation of enantiomeric mixtures to allow the preparation of a specific enantiomer of these substituted spiro-hydantoin compounds. Additionally, there exists a need for crystalline forms of the aryl and heteroaryl substituted spiro-hydantoins as well as certain intermediates which may exhibit desirable and beneficial chemical and physical properties.
The present invention is directed to these, as well as other important aspects.